TY - JOUR
T1 - Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses
AU - Jaynes, Jesse M.
AU - Sable, Rushikesh
AU - Ronzetti, Michael
AU - Bautista, Wendy
AU - Knotts, Zachary
AU - Abisoye-Ogunniyan, Abisola
AU - Li, Dandan
AU - Calvo, Raul
AU - Dashnyam, Myagmarjav
AU - Singh, Anju
AU - Guerin, Theresa
AU - White, Jason
AU - Ravichandran, Sarangan
AU - Kumar, Parimal
AU - Talsania, Keyur
AU - Chen, Vicky
AU - Ghebremedhin, Anghesom
AU - Karanam, Balasubramanyam
AU - Salam, Ahmad Bin
AU - Amin, Ruksana
AU - Odzorig, Taivan
AU - Aiken, Taylor
AU - Nguyen, Victoria
AU - Bian, Yansong
AU - Zarif, Jelani C.
AU - de Groot, Amber E.
AU - Mehta, Monika
AU - Fan, Lixin
AU - Hu, Xin
AU - Simeonov, Anton
AU - Pate, Nathan
AU - Abu-Asab, Mones
AU - Ferrer, Marc
AU - Southall, Noel
AU - Ock, Chan Young
AU - Zhao, Yongmei
AU - Lopez, Henry
AU - Kozlov, Serguei
AU - de Val, Natalia
AU - Yates, Clayton C.
AU - Baljinnyam, Bolormaa
AU - Marugan, Juan
AU - Rudloff, Udo
N1 - Funding Information:
We thank L. Roy for help with the medical illustrations and visual artwork. We thank the NCI Patient-Derived Models Repository (PDMR), NCI-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD (pdmr.cancer.gov) for PDX models 193399-133-R, 381576-328-R, 165739-295-R, and 466636-057-R and S. A. Rosenberg for the provision of melanoma cell line 2183.
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2020/2/12
Y1 - 2020/2/12
N2 - Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182–mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206high patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.
AB - Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182–mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206high patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.
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UR - http://www.scopus.com/inward/citedby.url?scp=85079334565&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aax6337
DO - 10.1126/scitranslmed.aax6337
M3 - Article
C2 - 32051227
AN - SCOPUS:85079334565
SN - 1946-6234
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 530
M1 - eaax6337
ER -